Fulvestrant formulations

ABSTRACT

Fulvestrant formulations suitable for intramuscular injection at concentration in excess of 40 mg/ml in the absence of castor oil and castor oil derivatives are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 16/508,741, filedJul. 11, 2019, which is a continuation of U.S. Ser. No. 15/789,267,filed Oct. 20, 2017, now U.S. Pat. No. 10,363,259, which is acontinuation of U.S. Ser. No. 14/934,428 filed Nov. 6, 2015, now U.S.Pat. No. 9,801,892, which is a Divisional of U.S. patent applicationSer. No. 12/380,968 filed on Mar. 5, 2009, now U.S. Pat. No. 9,180,088which, in turn claims the benefit of priority from of U.S. ProvisionalApplication No. 61/068,560, filed Mar. 7, 2008, the contents of each ofwhich are incorporated herein by reference in their entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable

FIELD OF THE INVENTION

The present invention relates to fulvestrant formulations, especially toinjectable formulations of fulvestrant, and particularly tointramuscular injectable formulations. The invention also related to thesolvents glycofurol, poloxamer, reverse poloxamer, polyethylene glycol,propylene glycol, and dihydrolipoic acid.

BACKGROUND OF THE INVENTION

Fulvestrant Injection for intramuscular administration is an estrogenreceptor antagonist without known agonist effects and is marketed byAstra-Zeneca under trade name Faslodex®. The chemical name is7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl)nonyl]estra-1,3,5-(10)-triene-3,17-beta-diol. The molecular formula isC₃₂H₄₇F₅O₃S and its structural formula is:

Fulvestrant is a white powder with a molecular weight of 606.77. Thesolution for injection (as currently marketed) is a clear, colorless toyellow, viscous liquid. Each injection of the currently marketedFASLODEX contains as inactive ingredients: Alcohol, USP; Benzyl Alcohol,NF; and Benzyl Benzoate, USP, as co-solvents; and Castor Oil, USP as aco-solvent and release rate modifier. Its manufacture and general useare disclosed in U.S. Pat. No. 4,659,516, which is incorporated hereinby reference in its entirety.

FASLODEX is supplied in sterile single patient pre-filled syringescontaining 50 mg/ml fulvestrant either as a single 5 ml or twoconcurrent 2.5 ml injections to deliver the required monthly dose.Fulvestrant is currently labeled in the currently marketed FASLODEXproduct to be administered as an intramuscular injection of 250 mg oncemonthly.

A formulation of fulvestrant for intramuscular injection is disclosed inU.S. Pat. No. 6,774,122, which is incorporated herein by reference inits entirety. The formulation claimed in that patent is a fulvestrantsolution in a ricinoleate vehicle that additionally has at least onealcohol and a non-aqueous solvent which is miscible with the ricinoleatevehicle. The currently marketed FASLODEX injection product contains, inaddition to the fulvestrant; alcohol USP; benzyl alcohol; benzylbenzoate; and castor oil. Castor oil administration by injection hasbeen associated with potential side effects. In fulvestrant formulationshaving castor oil, injection site irritation is one of the most commonside effects. Ricinoleate (the major component of castor oil) is anintestinal secretogogue. Zinc ricinoleate has been found to be asensitizer in deodorants in which it has been incorporated. Sodiumricinoleate has been found to have membrane disruptive effects. Type IVdermal sensitization response in those previously sensitized toricinoleate have been attributed to ricinoleate administration. U.S.Pat. No. 5,462,726 is directed to a method of reducing, inhibiting, ortreating the unwanted side effects of castor oil in a solvent in a drugformulation by administering a thromboxane A₂ receptor antagonist. Thus,it is clear that the art recognizes there are concerns aboutadministering castor oil and castor oil derivatives as pharmaceuticalexcipients, especially by injection or transdermal routes. And, whilethese side effects may have to be accepted when there is no othermaterial which is suitable for administering a drug in an appropriatemanner, the search for a suitable alternative without these sideeffects, or lesser degree of these side effects, continues, and thediscovery of such an appropriate alternative would meet a long feltunmet need in the art.

In addition, there has been increasing interest in administration offulvestrant at doses in excess of the currently labeled amounts, up toand including as much as 1 gram per month. To do so with currentformulations, would currently require considerably larger volumes thancould be injected intramuscularly at any one time (5 ml being about themost possible), use of multiple injection sites, or administration atmultiple times throughout the month. Ideally, one would like toadminister the full desired dose at one time and at one injection site.With the currently marketed fulvestrant products, this is currentlyimpossible. Thus the search for injectable formulations of fulvestrantthat can deliver more than 250 mg in less than 5 ml of formulation is asought after end in the art.

OBJECTS OF THE INVENTION

It is therefore an object of the invention to provide a formulation offulvestrant that is suitable for injection purposes that issubstantially free of, if not totally free of, castor oil and castor oilderivatives.

It is a further object of the invention is to provide a method ofadministering fulvestrant by injection that is substantially free of, ifnot totally free of, injection site irritation.

It is yet another object of the invention is to provide an intramuscularinjection formulation of fulvestrant being substantially free, if nottotally free of, castor oil and castor oil derivatives.

Still another object of the invention is to provide a method ofadministering fulvestrant by intramuscular injection that issubstantially free of, if not totally free of, injection siteirritation.

Still an additional object of the invention is to provide a method ofadministering the recommended dose of fulvestrant with reduced volume(i.e., 1-4 ml relative to currently marketed Faslodex of 5 ml) at theinjection site.

Yet another object of the invention is to provide an injectableformulation of fulvestrant that can deliver dosages of up to 1 gram offulvestrant in volumes of less than 5 ml of formulation.

A further object of the invention is to provide a transdermaladministrable formulation of fulvestrant that is substantially free, ifnot totally free of, castor oil and castor oil derivatives.

An even further object of the invention is to provide a method ofadministering a fulvestrant formulation transdermally that issubstantially free of side effects associated with castor oil and castoroil derivatives.

A still further object of the invention is the provision of afulvestrant formulation for injection or transdermal administration inwhich the fulvestrant is present in a vehicle containing at least onesolvent selected from polyethylene glycol, propylene glycol, glycofurol,poloxamer, reverse poloxamer, dihydrolipoic acid, mixtures thereof, andnon-aqueous solutions of the foregoing.

An even further object of the invention is to provide an intramuscularinjection dosage form of fulvestrant that is capable of delivering atherapeutically effective amount of fulvestrant in less than 5 ml offormulation.

Still another object of the invention is to provide a fulvestrantintramuscular injection dosage form that can deliver a therapeuticallyeffective amount of fulvestrant in a single injection of about or lessthan 2.5 ml of formulation.

Still another object of the invention is to provide a fulvestrantintramuscular injection dosage form that can deliver a therapeuticallyeffective amount of fulvestrant in a single injection of about or lessthan 1.5 ml of formulation.

Yet another object of the invention is the provision of an intramuscularinjection dosage form of fulvestrant capable of delivering up to and/orin excess of 500 mg of fulvestrant in a single injection of less than orabout 5 ml of formulation.

An even further object of the invention is the provision of anintramuscular injection dosage form of fulvestrant capable of deliveringup to and/or in excess of 500 mg of fulvestrant in a single injection ofless than or about 2 ml of formulation.

Still further objects of the invention will be appreciated by those ofordinary skill in the art once familiar with the disclosures set forthherein.

BRIEF SUMMARY OF THE INVENTION

In a first embodiment of the invention in which a dosage form suitablefor administering currently recommended therapeutic doses of up to 250mg of fulvestrant as a single injection or in two injections, theforgoing and other objects of the invention can be achieved by acomposition comprising (1) fulvestrant in a concentration of at least 40mg/ml in (2) a solvent or solvent system, wherein said solvent orsolvent system is selected from the group consisting of glycofurol,polyethylene glycol, poloxamer, reverse poloxamer, propylene glycol,dihydrolipoic acid and mixtures thereof as well as substantiallynon-aqueous solutions thereof provided that (a) glycofurol ordihydrolipoic acid be a constituent of the solvent system or (b) ifneither glycofurol nor dihydrolipoic acid is a component of the solventsystem then the solvent system contain at least polyethylene glycol incombination with at least one of a poloxamer, a reverse poloxamer, orpropylene glycol; and (3) optionally containing other compatibleexcipients with the proviso that the formulations are substantially freeof, preferably completely free of, castor oil and castor oilderivatives. These formulations are preferably administeredintramuscularly, but can be administered by suitable injection routesthat are suitable for the fulvestrant active agent, or via transdermaladministration or topical administration.

In a second embodiment of the invention, the foregoing and other objectsof the invention can be achieved by substantially higher concentrationsof fulvestrant in a solvent or solvent system selected from the samegroup as set forth above for the first embodiment except that propyleneglycol can only be present if at least one of glycofurol ordihydrolipoic acid is present or if the solvent system is polyethyleneglycol/propylene glycol in the absence of a substantial amount ofpoloxamer or reverse poloxamer.

In both of the foregoing embodiments, castor oils and castor oilderivatives such as partially and fully hydrogenated versions of castoroil or polyethoxylated versions of either are substantially absent, ifnot totally absent, as defined further herein below.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

Not Applicable

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to formulations of fulvestrant thatare primarily designed for intramuscular injection, although otherinjection routes that are compatible with fulvestrant and the excipientsare also contemplated as within the invention. In addition,administration by transdermal or topical administration where desiredare also within the scope of the invention. The main features of theinvention formulation are (1) fulvestrant is contained within theformulation in a concentration of at least 40 mg/ml, preferably in afirst embodiment at a concentration of about 45 to about 60 mg/ml, morepreferably about 50 mg/ml and in a second embodiment in excess of 50mg/ml generally up to about 500 mg/ml (although even higherconcentrations are achievable), preferably about 75 mg/ml or more, morepreferably about 100 mg/ml or more, other preferred amounts includingabout 150 mg/ml or more, about 200 mg/ml or more, about 250 mg/ml, about300 mg/ml or more, about 375 mg/ml or more, about 400 mg/ml or more,about 450 mg/ml or more, and about 500 mg/ml or more, althoughconcentrations greater than about 300 mg/ml are generally too viscousfor intramuscular injection, such formulations remain suitable fortopical and transdermal administration of fulvestrant; (2) theformulation contains a solvent or mixed solvent system selected from thegroup consisting of (A) (i) glycofurol, (ii) dihydrolipoic acid, and(iii) mixtures thereof; each alone or (B) mixtures of any of theforegoing with one or more materials selected from the group consistingof polyethylene glycol, poloxamer, reverse poloxamer, and propyleneglycol, or (C) polyethylene glycol in combination with either apoloxamer, a reverse poloxamer or or propylene glycol, although thissection (C) solvent groups containing propylene glycol are only suitableup to concentrations of up to fulvestrant 50 mg/ml; in further optionalcombination with additional compatible solvents; (3) optionallyadditional pharmaceutically acceptable and compatible non-solventexcipients; and (4) the formulations are at least substantially free ofcastor oil and castor oil derivatives or completely free of castor oiland castor oil derivatives.

In other words, the solvent systems require use of one of

glycofurol,

glycofurol/polyethylene glycol,

glycofurol/propylene glycol,

glycofurol/polyethylene glycol/propylene glycol,

glycofurol/poloxamer,

glycofurol/poloxamer/propylene glycol,

glycofurol/reverse poloxamer,

glycofurol/reverse poloxamer/propylene glycol,

glycofurol/poloxamer/polyethylene glycol,

glycofurol/poloxamer/polyethylene glycol/propylene glycol,

glycofurol/reverse poloxamer/polyethylene glycol,

glycofurol/reverse poloxamer/polyethylene glycol/propylene glycol,

glycofurol/poloxamer/reverse poloxamer,

glycofurol/poloxamer/reverse poloxamer/polyethylene glycol,

glycofurol/poloxamer/reverse poloxamer/propylene glycol,

glycofurol/poloxamer/reverse poloxamer/polyethylene glycol/propyleneglycol,

dihydrolipoic acid,

dihydrolipoic acid/polyethylene glycol,

dihydrolipoic acid/propylene glycol,

dihydrolipoic acid/polyethylene glycol/propylene glycol,

dihydrolipoic acid/poloxamer,

dihydrolipoic acid/poloxamer/propylene glycol,

dihydrolipoic acid/reverse poloxamer,

dihydrolipoic acid/reverse poloxamer/propylene glycol,

dihydrolipoic acid/poloxamer/polyethylene glycol,

dihydrolipoic acid/poloxamer/polyethylene glycol/propylene glycol,

dihydrolipoic acid reverse poloxamer/polyethylene glycol,

dihydrolipoic acid/reverse poloxamer/polyethylene glycol/propyleneglycol,

dihydrolipoic acid/poloxamer/reverse poloxamer,

dihydrolipoic acid/poloxamer/reverse poloxamer/polyethylene glycol,

dihydrolipoic acid/poloxamer/reverse poloxamer/propylene glycol,

dihydrolipoic acid/poloxamer/reverse poloxamer/polyethyleneglycol/propylene glycol,

glycofurol/dihydrolipoic acid,

glycofurol/dihydrolipoic acid/polyethylene glycol,

glycofurol/dihydrolipoic acid/propylene glycol,

glycofurol/dihydrolipoic acid/polyethylene glycol/propylene glycol,

glycofurol/dihydrolipoic acid/poloxamer,

glycofurol/dihydrolipoic acid/poloxamer/propylene glycol,

glycofurol/dihydrolipoic acid/reverse poloxamer,

glycofurol/dihydrolipoic acid/reverse poloxamer/propylene glycol,

glycofurol/dihydrolipoic acid/poloxamer/polyethylene glycol,

glycofurol/dihydrolipoic acid/poloxamer/polyethylene glycol/propyleneglycol,

glycofurol/dihydrolipoic acid reverse poloxamer/polyethylene glycol,

glycofurol/dihydrolipoic acid/reverse poloxamer/polyethyleneglycol/propylene glycol,

glycofurol/dihydrolipoic acid/poloxamer/reverse poloxamer,

glycofurol/dihydrolipoic acid/poloxamer/reverse poloxamer/polyethyleneglycol,

glycofurol/dihydrolipoic acid/poloxamer/reverse poloxamer/propyleneglycol,

glycofurol/dihydrolipoic acid/poloxamer/reverse poloxamer/polyethyleneglycol/propylene glycol,

polyethylene glycol/propylene glycol,

poloxamer/polyethylene glycol,

reverse poloxamer/polyethylene glycol,

poloxamer/polyethylene glycol/propylene glycol,

reverse poloxamer/polyethylene glycol/propylene glycol,

poloxamer/reverse poloxamer/polyethylene glycol,

poloxamer/reverse poloxamer/polyethylene glycol/propylene glycol,

and substantially non-aqueous solutions thereof and optionallycontaining other compatible excipients with the proviso that theformulations are substantially free of, preferably completely free of,castor oil and castor oil derivatives. These formulations are preferablyadministered intramuscularly, but can be administered by other suitableinjection routes that are suitable for the fulvestrant active agent, orvia transdermal or topical administration.

In a second embodiment of the invention, the foregoing and other objectsof the invention can be achieved by substantially higher concentrationsof fulvestrant in a solvent or solvent system selected from theforegoing group of solvent systems except that if propylene glycol isused, it is only used when glycofurol or dihydrolipoic acid is alsopresent, preferably for this embodiment, propylene glycol is not used atall. In other words, for this second embodiment in which greater than 50mg/ml solutions of fulvestrant in the solvent or solvent system arerequired, the solvent or solvent system is selected from

glycofurol,

glycofurol/polyethylene glycol,

glycofurol/propylene glycol,

glycofurol/polyethylene glycol/propylene glycol,

glycofurol/poloxamer,

glycofurol/poloxamer/propylene glycol,

glycofurol/reverse poloxamer,

glycofurol/reverse poloxamer/propylene glycol,

glycofurol/poloxamer/polyethylene glycol,

glycofurol/poloxamer/polyethylene glycol/propylene glycol,

glycofurol reverse poloxamer/polyethylene glycol,

glycofurol/reverse poloxamer/polyethylene glycol/propylene glycol,

glycofurol/poloxamer/reverse poloxamer,

glycofurol/poloxamer/reverse poloxamer/polyethylene glycol,

glycofurol/poloxamer/reverse poloxamer/propylene glycol,

glycofurol/poloxamer/reverse poloxamer/polyethylene glycol/propyleneglycol,

dihydrolipoic acid,

dihydrolipoic acid/polyethylene glycol,

dihydrolipoic acid/propylene glycol,

dihydrolipoic acid/polyethylene glycol/propylene glycol,

dihydrolipoic acid/poloxamer,

dihydrolipoic acid/poloxamer/propylene glycol,

dihydrolipoic acid/reverse poloxamer,

dihydrolipoic acid/reverse poloxamer/propylene glycol,

dihydrolipoic acid/poloxamer/polyethylene glycol,

dihydrolipoic acid/poloxamer/polyethylene glycol/propylene glycol,

dihydrolipoic acid reverse poloxamer/polyethylene glycol,

dihydrolipoic acid/reverse poloxamer/polyethylene glycol/propyleneglycol,

dihydrolipoic acid/poloxamer/reverse poloxamer,

dihydrolipoic acid/poloxamer/reverse poloxamer/polyethylene glycol,

dihydrolipoic acid/poloxamer/reverse poloxamer/propylene glycol,

dihydrolipoic acid/poloxamer/reverse poloxamer/polyethyleneglycol/propylene glycol,

glycofurol/dihydrolipoic acid,

glycofurol/dihydrolipoic acid/polyethylene glycol,

glycofurol/dihydrolipoic acid/propylene glycol,

glycofurol/dihydrolipoic acid/polyethylene glycol/propylene glycol,

glycofurol/dihydrolipoic acid/poloxamer,

glycofurol/dihydrolipoic acid/poloxamer/propylene glycol,

glycofurol/dihydrolipoic acid/reverse poloxamer,

glycofurol/dihydrolipoic acid/reverse poloxamer/propylene glycol,

glycofurol/dihydrolipoic acid/poloxamer/polyethylene glycol,

glycofurol/dihydrolipoic acid/poloxamer/polyethylene glycol/propyleneglycol,

glycofurol/dihydrolipoic acid reverse poloxamer/polyethylene glycol,

glycofurol/dihydrolipoic acid/reverse poloxamer/polyethyleneglycol/propylene glycol,

glycofurol/dihydrolipoic acid/poloxamer/reverse poloxamer,

glycofurol/dihydrolipoic acid/poloxamer/reverse poloxamer/polyethyleneglycol,

dihydrolipoic acid/poloxamer/reverse poloxamer/propylene glycol,

glycofurol/dihydrolipoic acid/poloxamer/reverse poloxamer/polyethyleneglycol/propylene glycol,

polyethylene glycol/propylene glycol,

poloxamer/polyethylene glycol,

reverse poloxamer/polyethylene glycol,

poloxamer/reverse poloxamer/polyethylene glycol,

and substantially non-aqueous solutions thereof and optionallycontaining other compatible excipients with the proviso that theformulations are substantially free of, preferably completely free of,castor oil and castor oil derivatives. These formulations are preferablyadministered intramuscularly, but can be administered by other suitableinjection routes that are suitable for the fulvestrant active agent, orvia transdermal or topical administration.

For purposes of the present invention, substantially free, whenreferencing the amount of a component of a formulation means not morethan about 5%, preferably not more than about 4.5%, more preferably notmore than about 4%, even more preferably not more than about 3%, stillmore preferably not more than about 2%, yet more preferably not morethan about 1%, still more preferably not more than about 0.5%, evenstill more preferably not more than about 0.1%, still more preferablynot more than about 0.01% (100 ppm), most preferably undetectableamounts with the use of standard analytic equipment as of the filingdate of the present specification, (i.e., zero), each of the %s beingwith reference to the complete formulation. In addition, with referenceto the absence of castor oil or castor oil derivative associated sideeffects, the term “substantially free of” means that the presentinvention has a significantly lesser rate of incidence of that sideeffect in test populations as compared to formulations having the samepercentage of castor oil as present in the FASLODEX marketed product assold in the US as of the filing date of the present invention and/or(preferably and) an absolute rate of incidence of such side effect ofnot more than about 10% of the test population, preferably not more thanabout 5% of the test population, even more preferably not more thanabout 2% of the test population, still more preferably not more thanabout 1% of the test population, even more preferably not more thanabout 0.5% of the test population.

Alternatively, “substantially free” with respect to the avoidance ofside effects also means a reduction in or avoidance of such side effectwith respect to the degree of such side effect seen in patients giventhe present invention as compared to that degree seen in patientsgenerally given similar formulations having castor oil or castor oilderivatives in amounts present in the FASLODEX marketed product as soldin the US as of the filing date of the present invention. Thus, bothabsolute rate of side effect presentation (described in the previousparagraph) and degree of reduction of that side effect independently canbe the basis for “substantial free” when speaking of side effect issues,preferably both incidence and degree of side effect reduction meet theselimitations simultaneously. In this context (side effect issues),“substantially free” means less than 20% of that seen with the currentmarked FASLODEX product (independently with respect to rate of sideeffect presentation and/or side effect level), preferably less thanabout 10%, more preferably less than about 7.5%, still more preferablyless than about 5%, even more preferably less than about 2.5%, stillmore preferably less than about 1%, most preferably 0% of that seen withthe FASLODEX product. Preferably, the products of the present inventionmeet each of (1) the absolute amount “substantially free” limitation oncastor oil and castor oil derivative and (2) at least one of the“substantially free” limitations (a) on side effect per se or (b) rateof side effect in test populations.

For purposes of the present invention, one must find a solvent orsolvent system that is (a) capable of solubilizing fulvestrant to theappropriate degree; (b) be a solvent that is administrable viainjection, especially intramuscularly, or via the transdermal or topicalroute; and (c) that is substantially free of or completely free of theside effects typically attributable to castor oil or castor oilderivatives upon injection. The typical side effects of castor oil andits derivatives are (a) skin and other irritation at the administrationsite; (b) allergic reaction; and (c) gastrointestinal disturbances eventhough the product is not administered to the GI tract. While any one ormore of these can serve as a basis of improvement, the primary (but notexclusive) measure of whether the invention product is “substantiallyfree” of the “castor oil associated side effects” is skin or injectionsite irritation. Preferably more than one of these side effects, andmost preferably all of these side effects have a lesser rate ofpresentation and lower severity when present than that seen in thecurrently US marketed FASLODEX product.

In examining the solubility of fulvestrant, the following table showsthat there are few solvents that are truly capable of meeting even theat least 40 mg/ml solubility requirement.

Tween 80(1%) Insoluble Lecithin (1%) Insoluble Lecithin (1%) InsolubleLecithin (1%) Insoluble Tween 20(1%) Insoluble Sodium Citrate (30 Mmol)Insoluble Hydroxy Ethyl Starch (10%) Insoluble N-Methylpyrrolidone 864mg/ml Aq. PVP K-30 solution (40 mg in 2 ml distil water) InsolubleT-butanol 194 mg/ml 1,4 Dioxan 833 mg/ml TPGS 1000 Insoluble Ethylacetate 7.8 mg/ml Peanut Oil Insoluble Fat emulsion Insoluble Poloxamer(Lutrol f-68)(2% sol in water) Insoluble Lauryl macrogol - 32 glyceride(Gelucire 44/14 ® by Insoluble Gattefosse) 10% Ethanol Insoluble 10%Ethanol (in water) + PEG 400 (1:1) Insoluble 30% Ethanol (in water)Insoluble 50% Ethanol (in water) Insoluble 2% Benzyl alcohol in WaterInsoluble 0.9% Benzyl alcohol in Water Insoluble Propylene Glycol 4.0mg/ml PEG-400 22.5 mg/ml 10% Ethanol/0.9% Benzyl alcohol in PEG 400 10mg/ml (50 ml solution contains 10% ethanol and 0.9% benzyl alcohol andQS to 50 ml with PEG 400 (V/V)) 10% Ethanol/0.9% Benzylalcohol/30% PEG400 in 10 mg/ml Water (50 ml contains 10% ethanol, 0.9% BA, 30% PEG 400all (v/v) qs with water) 10% Ethanol/0.9% Benzylalcohol/30% PEG 400/20mg 5 mg/ml per ml Lecithin, in Water (50 ml contains 10% ethanol, 0.9%BA, 30% PEG 400 all (v/v) + 20 mg/ml Lecithin and qs with water PEG400 + PG (1:1) 50 mg/ml Cetyl alcohol 20 mg/1 g 20 mg/ml of Lutrol in PG22.7 mg/ml 0.8 ml of (20 mg/ml of Lutrol in PEG 400) + 50 mg/ml 0.2 mlof Propylene Glycol 0.7 ml of (20 mg/ml of Lutrol in PEG 400) + 50 mg/ml0.3 ml of Propylene Glycol 20 mg/ml of Lutrol in PEG 400 66.7 mg/mlGlycofurol 400 mg/ml Dihydrolipoic acid >450 mg/ml 20-50 mg/ml Lutrol indihydrolipoic acid >350 mg/ml 50% dihydrolipoic acid/50% lipoicacid >350 mg/ml

From the above table, it is clear that of the foregoing list, onlyN-methylpyrrolidone, t-butanol, PEG 400+propylene glycol (1:1), 2%solution of Lutrol (poloxamer) in PEG 400, 2% solution of Lutrol in PEG400 with propylene glycol, glycofurol, dihydrolipoic acid, andpoloxamer/dihydrolipoic acid solubilize fulvestrant sufficiently to beable to have a final concentration of fulvestrant of at least 40 mg/mlbased on the complete formulation, and only those solvent systems havingglycofurol or dihydrolipoic acid as a component sufficiently solubilizethe fulvestrant to be able to achieve the second embodiment of thepresent invention of substantially higher concentration formulations(greater than 50 mg/ml), although 2% solution of Lutrol (poloxamer) inPEG 400 falls within the lower end of the second embodiment.

Furthermore, the solubility of fulvestrant in 1:1 PEG 400 and propyleneglycol is quite surprising as solubility in neat (100%) propylene glycolwas only 4 mg/ml, and in neat (100%) PEG-400 was only 22.5 mg/ml, whilein 1:1 PEG-400 and propylene glycol system, the solubility is 50 mg/ml.It is equally surprising that solubility in the Lutrol/PEG400/propyleneglycol blends was 50 mg/ml as it was insoluble in the neat 2% Lutrolsolution, 4mg/ml in the neat propylene glycol, and 22.5mg/ml in the neatPEG 400. It is still additionally surprising that fulvestrant wassoluble at 66.7 mg/ml in 2% Lutrol in PEG 400 without the propyleneglycol.

While N-methylpyrrolidone and 1.4-dioxane (and even t-butanol) areexcellant solubilizers for fulvestrant, each of these have their ownsignificant side effects that make them unsuitable for use in injectableformulations. Advantageously, the present invention permits fulvestrantcontaining formulations containing up to and in excess of 250 mg/mlfulvestrant. Preferably embodiments contain fulvestrant in amounts ofabout 45 mg/ml, about 50 mg/ml, about 55 mg/ml, about 60 mg/ml, about 65mg/ml, about 70 mg/ml, about 75 mg/ml, about 80 mg/ml, about 85 mg/ml,about 90 mg/ml, about 95 mg/ml, about 100 mg/ml, about 105 mg/ml, about110 mg/ml, about 115 mg/ml, about 120 mg/ml, about 125 mg/ml, about 130mg/ml, about 135 mg/ml, about 140 mg/ml, about 145 mg/ml, about 150mg/ml, about 155 mg/ml, about 160 mg/ml, about 165 mg/ml, about 170mg/ml, about 175 mg/ml, about 180 mg/ml, about 185 mg/ml, about 190mg/ml, about 195 mg/ml, about 200 mg/ml, about 205 mg/ml, about 210mg/ml, about 215 mg/ml, about 220 mg/ml, about 225 mg/ml, about 230mg/ml, about 235 mg/ml, about 240 mg/ml, about 245 mg/ml, about 250mg/ml, about 275 mg/ml, about 300 mg/ml, about 325 mg/ml, about 350mg/ml, about 375 mg/ml, about 400 mg/ml, about 425 mg/ml, about 450mg/ml, about 475 mg/ml, or about 500 mg/ml (although concentrations of400 mg/ml and higher are generally too viscous for intramuscularinjection, these are still suitable for topical and transdermaladministration), and can contain lesser amounts per ml if desired aswell as any amount falling between any of the specifically recitedamounts. Fulvestrant dissolved in 100% glycofurol or in mixtures ofglycofurol with PEG or mixtures of glycofurol with poloxamer orfulvestrant dissolved in 100% dihydrolipoic acid or mixtures ofpoloxamer and dihydrolipoic acid, or mixtures having both glycofurol anddihydrolipoic acid are preferred for concentrations in excess of about95 mg fulvestrant/ml of formulation. The mixtures may be in anyproportion, but is preferred where the glycofurol (for glycofurolcontaining formulations) or dihydrolipoic acid (for formulationscontaining dihydrolipoic acid as the solvent) makes up at least 20% ofthe mixture of solvents. Very highly preferred are 1:1 mixtures ofglycofurol with either polyethylene glycol or propylene glycol as aremixtures of 20-50 mg of poloxamer/ml of dihydrolipoic acid and 20-50 mgploxamer per ml of 1:1 mixture of dihydrolipoic acid and lipoic acid.Other preferred solutions, especially when a solubility of about 50mg/ml or less is necessary include PEG/propylene glycol (1:1),2%poloxamer in PEG in combination with propylene glycol (with thepropylene glycol making up 20-30% of the solvent system), and 2%poloxamer in PEG. When polyethylene glycol (PEG) is used, it ispreferably PEG-200-800, more preferably PEG-400. Another preferredsolvent system is poloxamer generally about up to 4%, preferably about 1to about 3%, more preferably about 2% in polyethyleneglycol, preferablyin polyethylene glycol 400, glycofurol, or dihydrolipoic acid ormixtures thereof. Preferred poloxamers include, without limitationpoloxamer 188 and poloxamer 421 and the commercial material known asLUTROL (which is poloxamer 188, aka Pluronic F-68). Poloxamers are blockcopolymers having a central block of polypropyleneoxide bounded on eachside by a block of polyethylene oxide. Reverse poloxamers are blockcopolymers having a central block of polyethyleneoxide bounded on eachside by polypropyleneoxide. The reverse poloxamers can generally be usedin place of poloxamers in the same proportions as set forth for thepoloxamers. The reverse poloxamers and the poloxamers differ slightly intheir hydrophilic/hydrophobic nature and those of ordinary skill in theart would be able to make appropriate substitutions between poloxamersand reverse poloxamers for use in the instant invention in light of thisspecification.

Since a major point of the invention is to avoid the irritation at theadministration site, and thus hopefully achieve better compliance withthe full regimen recommended for the indications being treated,solubility is not the end of the determination of a suitable solvent orsolvent system. Irritation studies, as shown in the table belowdemonstrate the improvement seen with the present invention glycofuroland glycofurol/PEG formulations.

Test # Composition Irritation rating 01 Labrafac 1.25 ml StronglyIrritating PEG 400 0.625 ml PG 0.625 ml 02 Glycofurol No Irritation 03Glycofurol 0.75 ML No Irritation PEG 400 0.50 ML 04 Glycofurol 0.625 MLNo Irritation PEG 400 0.625 ML 05 Glycofurol 0.625 ML SlightlyIrritating PG 0.625 ML 06 PG Slightly Irritating 07 Labrafac StronglyIrritating 08 PEG 400 alone No Irritation 09 Marketed product's solventSlightly Irritating which system (consists of 10% Ethanol, is higherthan the 10% benzyl alcohol, 15% benzyl Glycofurol system and benzoateand qs to 100% (v/v) much lower than Labrafac with castor oil) systemThe above tests were conducted by injecting 0.1 ml of solvent system inrat tail vein and observing for signs of irritation. Irritability isgraded as per the observations of the behavior of the rat and also thesite of injection. If the rat is absolutely restless with continuousmovement within the cage, the solvent system is considered as stronglyirritation which coincides with the inflammation at the site ofinjection. Slightly irritating is considered to be the case when therat's behavior is slightly above the normal movement of the rat.

In addition, a rat paw lick test was conducted to further evaluate theirritation issue and the results are shown in the table below. In thismethod 0.1 ml of the solvent system is injected on the subplanar paw ofthe rat and the irritation is measured by the number of time that ratlicks its paw over 15 minutes. This is quite quantitative and the numberlicks correlate to the irritation of the system.

COMPOSITION IRRITABILITY Labrafac 1.25 ml Strongly Irritating. PEG 4000.625 ml  30 licks in first 15 minutes PG 0.625 ml  Glycofurol NoIrritation Zero lick in first 15 minutes Glycofurol 0.75 ml NoIrritation PEG 400 0.75 ml Zero lick in first 15 minutes Marketedproduct's solvent system Slightly irritating. 6 licks in first 15minutes Normal Saline control Zero licks in 15 minutesOf the solvent systems tested in the above tables, only glycofurol orglycofurol/PEG showed no irritation in each test, while the solventsystem in the currently marketed Faslodex product (containing castoroil) showed irritation in each of the tests.

Another factor of importance in the inventive formulations is theirstability over time so that a commercially reasonable product can bemanufactured and introduced into the channels of commerce withsufficient dating as to be commercially reasonable. Generally, a stableproduct is one which when stored under the directed conditions retainsat least 80% of label potency, preferably at least about 90% of labeledpotency at a designated date, which is generally at least one year,preferably at least about 18 months, more preferably at least about 2years, and most preferably even longer. Direct data on stability for theparticular time and storage conditions as well as accelerated stabilitystudies as are common in the art can be used to determine the particularformulation stability. An alternative demonstration for stability isbased on the area % detection of degradants over the particular timeperiod and storage conditions in question (i.e., direct storage oraccelerated stability storage conditions to allow for a dating of therespective time period in question, namely at least one year, preferablyat least 18 months, more preferably at least 2 years, most preferablylonger). Generally a stable product is one which has not more than atotal of area % of degradants of 3% and any one degradant area % of notmore than 1%, preferably both total degradant and any one degradantlimitations are simultaneously met. Preferably both potency anddegredant area % limitations are met.

In some embodiments, some oxidative degradation was seen andincorporation of a compatible antioxidant is of additional value.Suitable non-limiting antioxidants include, without limitation, lipoicacid and its structural analogs such as dihydrolipoic acid, methionineand other sulfur-containing amino acids, acetone sodium bisulfate,propyl gallate, BHT, BHA and sodium formaldehyde sulfoxylate. Preferablythe antioxidant is lipoic acid or its structural analogs such asdihydrolipoic acid, and preferably the antioxidant is present in anamount ranging up to about 75 mg/ml, more preferably about 25-75 mg/ml,still more preferably about 50 mg/ml. In addition, dihydrolipoic acidcan also be used as a solubilizing agent as well as a carrier solvent,which can further aid to prolong the release of drug as well as reducingthe injection volume. Because of these additional uses of dihydrolipoicacid, it may further be used beyond these “antioxidant” limitationamounts all the way up to the amounts indicated as suitable earlier foruse as a solvent.

The following examples are presented to exemplify, not limit, the scopeof the present invention, which is only limited by the claims appendedhereto.

General

The storage condition for the current commercial FASLODEX formulation is2-8° C. which means that the marketed product needs to be stored underrefrigerated conditions. In order to understand the degradation natureof fulvestrant, we conducted stability of fulvestrant in stronglyacidic, basic and peroxide media at 60° C. In acid, we stored thesamples for 7 days, in base for 5 days and in peroxide for 48 hour. Thedegradation profile is tabulated below:

Area % Area % Area % DEGRADENT DEGRADENT DEGRADENT DEGRADENT RRT In AcidIn Base In Peroxide 0.49 0.86 — — 0.52 2.31 — — 0.95 0.35 — — 1.07 0.520.54 28.3  1.12 0.86 — — 1.18 — — 0.39 1.20 — — 0.43The data suggest that fulvestrant is susceptible to oxidation and showeda better stability in the basic medium compared the acidic environment.In the next set of experiments, we prepared a simulated version ofFASLODEX using the same components as set forth in the FASLODEX labeland is shown below:

-   -   Fulvestrant 50 mg/mL    -   Ethanol (Dehydrated) 10% w/v    -   Benzyl Alcohol 10% w/v    -   Benzyl Benzoate 15% w/v    -   Castor Oil q.s. to volume.

The required quantity of fulvestrant was weighed and taken in aVolumetric Flask. Ethanol was added to this and sonicated for 5 mingiving a clear solution. Benzyl alcohol and benzyl benzoate were addedas per formula and mixed thoroughly to obtain a clear solution. CastorOil was added to make up the volume. The solution was stored at 40° C.for three months. The purpose of the study is to determine thedegradation profile of simulated FASLODEX formulation. The degradationproduct summary is presented in table 2:

TABLE 2 Degradation profile of simulated innovator product stored at 40°C. for 3 months Impurity Impurity RRT Area % ID 1.06 0.26 Unknown 1.0812.9 Oxidation 1.16 0.25 Unknown 1.18 0.09 Oxidation 1.20 0.15 OxidationAs shown in the table above, the formulation showed significantoxidative degradation. Therefore, we tested several innovativeformulations that contain various combinations of drug concentration,PEG400, glycofurol, lutrol with and without antioxidizing agents. Thedata summarized in the following examples.

EXAMPLE 1

Fulvestrant: 100 mg/ml In a solvent system of Labrofac 50% PG 25% PEG400 25%The above formulation is stored under the conditions set forth in theTable below and the degradation profile is set out in the Table.

Storage Time Initial Impurity Temp. period Content as 100% RRT Area %Initial 133.0 100 1.10 0.39 1.22 0.11 40 90 days 97.0 73 1.06 0.14 1.070.23 1.09 0.88 1.18 0.13 1.22 0.11The formulation showed a better degradation profile compare to thesimulated innovator formulation. We observed 13.7% area percent ofdegradants in the simulated Falsodex compared to 1.5% of the inventiveformulation presented in the Example 1. Moreover a single oxidant peakof 12.8 area percent was observed in the simulated Falsodex formulation.

EXAMPLE 2

The following formulation was prepared and tested for stability overtime.

Fulvestrant: 25 mg/ml in Glycofurol 100% Storage Time Initial ImpurityTemp. period Content as 100% RRT Area % Initial 25.5 100 1.07 0.36 1.100.10 40° C. 60 days 24.1 95 1.07 3.94 1.17 0.27 1.19 0.10 90 days 22.387 1.06 6.14 1.15 0.35 1.17 0.09 1.19 0.21 25° C. 3 months 24.5 96 1.061.22 1.15 0.05 1.17 0.09 6 months 24.0 94 0.07 0.13 1.08 2.40 1.21 0.111.23 0.12 12 months 23.1 91 1.07 6.49 1.14 0.12 1.16 0.33 1.18 0.16 1.190.72 1.21 0.18 1.23 0.26 1.24 0.25 1.25 0.15Fulvestrant showed much better stability in the glycofurol containingmedium compared to the mixed solvent system presented in the Example 1.Once again the predominant degradation path is oxidative degradation.More degradant peaks observed at 12month storage at 25° C. compared tosix months sample and the peak at RRT about 1.07 is the major degradant.

EXAMPLE 3

In the next set of experiments, we prepared fulvestrant at 150 mg/ml inglycofurol and its stability was evaluated. The purpose of thisexperiment is to evaluate whether higher concentration of fulvestrantwould affect the stability.

Storage Time Initial as Temp. period Content 100% Initial 157.7 100 40°C. 30 days 88.3 56 60 days 82.4 52 90 days 74.2 47 25° C. 3 months 150.495

This formulation showed inferior stability compared to Example 2 underaccelerated conditions.

EXAMPLE 4 & EXAMPLE 5

Since 150 mg/ml fulvestrant in glycofurol showed poor stability comparedto 25 mg/ml under accelerated conditions, we have conducted thestability of fulvestrant at 75 mg/ml and 50 mg/ml in glycofurol. Thestability data presented in the tables below:

50 MG/ML Storage Time Content Initial as Temp. period mg/ml 100% Initial47.8 100 40° C. 30 days 47.0 98 60 days 45.6 95 90 days 42.8 90 25° C. 3months 45.6 95 6 months 45.4 95 12 months 44.5 93

75 MG/ML Storage Time Content Initial as Temp. period mg/ml 100% Initial77.8 100 40° C. 30 days 74.9 96 60 days 70.5 91 90 days 67.5 87 25° C. 3months 74.9 96 6 months 71.2 92 9 months 69.0 89The 75 mg/ml and 50 mg/ml formulations show better stability than theconcentrated 150 mg/ml formulation.

EXAMPLE 6

We have also studied the stability of fulvestrant at 200 mg/ml in asolvent system that contained 50% glycofurol/50% propylene glycol. Thestability data presented in the table below

Storage Time Content Initial as Temp. period mg/ml 100% Initial 198.0100 40° C. 30 days 197.0 100 60 days 195.2 99 90 days 191.6 97 25° C. 3months 198.5 100 6 months 195.0 98.5 12 months 187.0 94.4Fulvestrant showed outstanding stability in this system. The acceleratedstability data indicate that this formulation is stable for 2 years atroom temperature storage. Also, we did not find any significant levelsof oxidative degradation this system, suggesting that the combination ofpropylene glycol and glycofurol surprisingly prevents the oxidativedegradation. This is quite unusual as both these solvents are known topromote the oxidation.

EXAMPLE 7

We have also studied the stability of fulvestrant at 100 mg/ml in asolvent system that contained 50% glycofurol/50% PEG 400. The stabilitydata presented in the table below

Initial Area % Storage Time Content as of oxidative Temp. period mg/ml100% degredant Initial 94.5 100 0 40° C. 30 days 92.8 98 0.7 60 days92.8 98 1.0 90 days 89.7 94 1.1 25° C. 3 months 95.6 101 0 6 months 94.4100 0.8 12 months 92.3 98 1.2The stability of fulvestrant in this system is comparable toglycofurol/PG containing system.

EXAMPLE 8

Since fulvestrant undergoes oxidation, we also have evaluated the effectof an antioxidizing agent on the stability of the formulation of Example7. 50 mg/ml lipoic acid was also incorporated into the system. Thestability data is presented in the table below:

Initial Area % Storage Time as of oxidative Temp. period Content 100%degredant Initial 100.1 100 0 40° C. 30 days 97.6 98 0 60 days 97.5 97 090 days 95.2 95 0 25° C. 90 days 98 98 0 6 months 98 98 0 12 months 9797 0We have conducted bioequivalence study comparing this formulation withthe innovator product. The composition of the formulation we tested isas follows:

Ingredients per 2.5 ml Fluvestrant 250 PEG-400 1.25 ml Glycofurol 1.25ml α-lipoic acid 125 mgThe test results suggest that our formulation does sustain drug in thecirculation for 28 days, like the currently marketed FASLODEX productformulation.

EXAMPLE 9

A 50 mg/ml fulvestrant formulation using dihydrolipoic acid as a solventis prepared having the following components and amounts:

Fulvestrant: 50 mg Dihydrolipoic acid, quantity sufficient to make→ 1 ml50 mg of fulvestrant weighed into a 1 ml volumetric flask and dissolvedby adding 0.5 ml of dihydrolipoic acid. After complete dissolution, thecontents of the flask made to the volume by adding dihydrolipoic acid.

EXAMPLE 10

A 100 mg/ml fulvestrant formulation using dihydrolipoic acid as asolvent is prepared having the following components and amounts:

Fulvestrant: 100 mg Dihydrolipoic acid, quantity sufficient to make→ 1ml100 mg of fulvestrant is weighed into a 1 ml volumetric flask anddissolved by adding 0.5 ml of dihydrolipoic acid. After completedissolution, the content of the flask is made to the volume by addingdihydrolipoic acid.

EXAMPLE 11

A 150 mg/ml fulvestrant formulation using dihydrolipoic acid as asolvent is prepared having the following components and amounts:

Fulvestrant: 150 mg Dihydrolipoic acid, quantity sufficient to make→ 1ml

150 mg of fulvestrant is weighed into a 1 ml volumetric flask anddissolved by adding 0.5 ml of dihydrolipoic acid. After completedissolution, the content of the flask is made to the volume by addingdihydrolipoic acid.

EXAMPLE 12

A 250 mg/ml fulvestrant formulation using dihydrolipoic acid as asolvent is prepared having the following components and amounts:

Fulvestrant: 250 mg Dihydrolipoic acid, quantity sufficient to make→ 1ml

250 mg of fulvestrant is weighed into a 1 ml volumetric flask anddissolved by adding 0.5 ml of dihydrolipoic acid and sonicating thecontents of flask for 2 minutes. After complete dissolution, the contentof the flask is made to the volume by adding dihydrolipoic acid.

EXAMPLE 13

A 350 mg/ml fulvestrant formulation using dihydrolipoic acid as asolvent is prepared having the following components and amounts:

Fulvestrant: 350 mg Dihydrolipoic acid, quantity sufficient to make→ 1ml

350 mg of fulvestrant is weighed into a 1 ml volumetric flask anddissolved by adding 0.5 ml of dihydrolipoic acid and sonicating thecontents of flask for 5 minutes and heating to 60° C. for 10 minutes.After complete dissolution, the content of the flask is made to thevolume by adding dihydrolipoic acid.

EXAMPLE 14

A 500 mg/ml fulvestrant formulation using dihydrolipoic acid as asolvent is prepared having the following components and amounts:

Fulvestrant: 500 mg Dihydrolipoic acid, quantity sufficient to make→ 1ml

500 mg of fulvestrant is weighed into a 1 ml volumetric flask anddissolved by adding 0.5 ml of dihydrolipoic acid and sonicating thecontents of flask for 10 minutes and heating to 60° C. for 30 minutes.After complete dissolution, the content of the flask is made to thevolume by adding dihydrolipoic acid.

EXAMPLE 15

A 250 mg/ml fulvestrant formulation using dihydrolipoic acid/poloxameras a solvent is prepared having the following components and amounts:

Fulvestrant 250 mg Lutrol 20 mg Dihydrolipoic acid, quantity sufficientto make→ 1 ml

20 mg of lutrol is weighed into a 1 ml volumetric flask and dissolved byadding 0.5 ml of dihydrolipoic acid. 250 mg of fulvestrant is added tothe flask and the contents of the flask is dissolved by sonicating theflask for 10 minutes and heating to 60° C. for 10 minutes. Aftercomplete dissolution, the content of the flask is made to the volume byadding dihydrolipoic acid.

EXAMPLE 16

A 250 mg/ml fulvestrant formulation using dihydrolipoic acid/poloxameras a solvent with additional lipoic acid as antioxidant is preparedhaving the following components and amounts:

Fulvrestrant 250 mg Lutrol 20 mg Lipoic Acid 100 mg Dihydrolipoic acid,quantity sufficient to make→ 1 ml

20 mg of lutrol and 100 mg of lipoic acid are weighed into a 1 mlvolumetric flask and dissolved by adding 0.5 ml of dihydrolipoic acid.250 mg of fulvestrant is added to the flask and the content of the flaskis dissolved by sonicating the flask for 10 minutes and heating to 60°C. for 10 minutes. After complete dissolution, the contents of the flaskis made to the volume by adding dihydrolipoic acid.

EXAMPLE 17

A 250 mg/ml fulvestrant formulation using dihydrolipoicacid/polyethylene glycol as a solvent is prepared having the followingcomponents and amounts:

Fulvestrant: 250 mg PEG 400 0.5 ml Dihydrolipoic acid, quantitysufficient to make→ 1 ml

250 mg of fulvestrant is weighed into a 1 ml volumetric flask anddispersed by adding 0.5 ml of PEG 400. The contents of the flask aredissolved by adding 0.3 ml of dihydrolipoic acid and sonicating thecontents of flask for 2minutes. After complete dissolution, the contentof the flask is made to the volume by adding dihydrolipoic acid.

EXAMPLE 18

A 250 mg/ml fulvestrant formulation using dihydrolipoicacid/poloxamer/polyethylene glycol as a solvent is prepared having thefollowing components and amounts.

Fulvestrant: 250 mg PEG 400 0.5 ml Lutrol 20 mg Dihydrolipoic acid,quantity sufficient to make→ 1 ml

250 mg of Fulvestrant and 20 mg of lutrol are weighed into a 1 mlvolumetric flask and dispersed by adding 0.5 ml of PEG 400. The contentsof the flask are dissolved by adding 0.3 ml of dihydrolipoic acid andsonicating the contents of flask for 2 minutes. After completedissolution, the content of the flask is made up to volume by addingdihydrolipoic acid.

We claim:
 1. A fulvestrant formulation, comprising at least 40 mg/mlfulvestrant in a pharmaceutically acceptable vehicle therefor whichcomprises glycofurol, said formulation being substantially free ofcastor oil and castor oil derivatives.
 2. The fulvestrant formulation ofclaim 1, wherein the pharmaceutically acceptable vehicle issubstantially non-aqueous.
 3. The fulvestrant formulation of claim 1,that is stable at about 25° C. for a period of at least one year.
 4. Thefulvestrant formulation of claim 3, that is stable at about 25° C. for aperiod of at least two years.
 5. The fulvestrant formulation of claim 3,wherein stability is measured by decomposition of said fulvestrant andis deemed stable when at least 80% of the label amount remains in saidformulation at the end of said period.
 6. The formulation of claim 1,wherein said pharmaceutically acceptable vehicle further comprises asolvent selected from the group consisting of polyethylene glycol,propylene glycol, dihydrolipoic acid and mixtures thereof, alone oroptionally in combination with up to 4% poloxamer and/or reversepoloxamer, said poloxamer % based on the total of the other solventspresent, and optionally at least one antioxidant.
 7. The formulation ofclaim 6, wherein said polyethylene glycol is selected from polyethyleneglycol 200 to polyethylene glycol
 800. 8. The formulation of claim 6,wherein said polyethylene glycol is polyethylene glycol
 400. 9. Theformulation of claim 1 wherein said fulvestrant is present in an amountselected from about 45 mg/ml, about 50 mg/ml, about 55 mg/ml, about 60mg/ml, about 65 mg/ml, about 70 mg/ml, about 75 mg/ml, about 80 mg/ml,about 85 mg/ml, about 90 mg/ml, about 95 mg/ml, about 100 mg/ml, about105 mg/ml, about 110 mg/ml, about 115 mg/ml, about 120 mg/ml, about 125mg/ml, about 130 mg/ml, about 135 mg/ml, about 140 mg/ml, about 145mg/ml, about 150 mg/ml, about 155 mg/ml, about 160 mg/ml, about 165mg/ml, about 170 mg/ml, about 175 mg/ml, about 180 mg/ml, about 185mg/ml, about 190 mg/ml, about 195 mg/ml, about 200 mg/ml, about 205mg/ml, about 210 mg/ml, about 215 mg/ml, about 220 mg/ml, about 225mg/ml, about 230 mg/ml, about 235 mg/ml, about 240 mg/ml, about 245mg/ml, about 250 mg/ml, about 275 mg/ml, about 300 mg/ml, about 325mg/ml, about 350 mg/ml, about 375 mg/ml, about 400 mg/ml, about 425mg/ml, about 450 mg/ml, about 475 mg/ml, and about 500 mg/ml.
 10. Theformulation of claim 6, further comprising at least one antioxidant. 11.The formulation of claim 10, wherein said antioxidant is selected fromthe group consisting of lipoic acid, dihydrolipoic acid, methionine andother sulfa-containing amino acids, acetone sodium bisulfate, propylgallate, BHT, BHA and sodium formaldehyde sulfoxylate.
 12. Theformulation of claim 11, wherein said antioxidant is lipoic acid and ispresent in an amount of about 25-75 mg/ml.
 13. The formulation of claim12, wherein said antioxidant is lipoic acid and is present in an amountof about 50 mg/ml.
 14. A method of improving patient compliance with anintramuscular fulvestrant dosage regimen comprising administering aformulation of claim 1 to a patient in need thereof.
 15. A solvent blendfor fulvestrant having the ability to dissolve fulvestrant in excess of40 mg/ml, comprising: (A) glycofurol alone or in conjunction with one ormore members selected from the group consisting of polyethylene glycols,poloxamers, reverse poloxamers, propylene glycol, dihydrolipoic acid,and mixtures thereof; (B) dihydrolipoic acid alone or in conjunctionwith one or more members selected from the group consisting ofpolyethylene glycols, poloxamers, reverse poloxamers, and mixturesthereof; (C) polyethylene glycol in combination with at least one of apolxamer, a reverse poloxamer, or propylene glycol; and (D) optionally acompatible co-solvent compatible with fulvestrant; said solvent blendbeing substantially free of water, and substantially free of castor oiland castor oil derivatives.
 16. A method of administering fulvestrant ina single intramuscular injection in a dose from in excess of 250 mgcomprising preparing a formulation of claim 1 having a concentration offulvestrant in excess of 50 mg/ml and administering the same byintramuscular injection to a patient in need thereof.
 17. The method ofclaim 16, wherein said dose in excess of 250 mg is selected from about275 mg, about 300mg, about 325 mg, about 350 mg, about 375 mg, about400mg, about 425 mg, about 450 mg, about 500 mg, about 550 mg, about 600mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850mg, about 900 mg, about 950 mg, and about 1000 mg, and said dose iscontained in said formulation in a volume of less than about 5 ml.